Processes and intermediates for the preparation of 2-substituted benzaldehydes

ABSTRACT

Processes for preparing 2-substituted benzaldehydes of general formula (I), wherein: R 1  is CH 2  CH 2  --(L 1 ) p  --(CH 2 ) q  --(L 2 ) r  --CH 2  --(T) 2  --Z; L 1  and L 2  are independently CH 2  CH 2 , CH═CH or C.tbd.C; q is 0 to 8; p, r and s are independently 0 or 1; T is O, S, CH 2 , CH═CH, C.tbd.C; and Z is C 1-4  alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituted with CF 3 , C 1-4  alkyl, C 1-4  alkoxy, methylthio, or trifluoromethylthio; and R 2  and A are independently H, CF 3 , C 1-4  alkyl, F, Cl, Br or I; are useful for preparing pharmaceutically active compounds.

This application is a 35 USC 371 of PCT/US93/02803, filed Mar. 25, 1993.

FIELD OF THE INVENTION

This invention relates to novel intermediates and processes forpreparing useful intermediates in the synthesis of pharmaceuticallyactive agents.

BACKGROUND

2-Substituted benzaldehydes are useful intermediates for preparingpharmaceutically active compounds. For example, certain compounds whichare leukotriene antagonists and useful in the treatment of asthma may beprepared from 2-substituted benzaldehydes of the general formula(Ia):##STR2## wherein:

R_(x) is (L)_(a) --(CH₂)_(b) --(T)_(c) --M;

a is 0or 1;

b is 3 to 14;

c is 0 or 1;

L and T are independently sulfur, oxygen, or CH₂ ; and

M is C₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl,thienyl, cyclohexyl or phenyl optionally mono substituted with Br, Cl,CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylthio, or trifluoromethylthio;

R₂ and A are independently selected from H, CF₃, C₁₋₄ alkyl, C₁₋₄alkoxy, F, Cl, Br, I, OH, NO₂ or NH₂ ;

or R₁ and A are H and R₂ is (L)_(a) --(CH₂)_(b) --(T)_(c) --M wherein a,b, c, L, T, and M are as defined above.

Such compounds are disclosed, for instance in U.S. Pat. No. 4,820,719,U.S. Pat. No. 4,874,792 and EP-A 0 296 732, the disclosures of which areincorporated herein by reference. Accordingly, two general methods forpreparing the 2-substituted benzaldehydes are reported therein: 1)palladium catalyzed addition of a substituted 1-alkynyl compound to a2-halo benzaldehyde effects a coupling to provide a2-(1-alkynyl)benzaldehyde directly, and 2) a 2-methoxy-benzoic acid maybe converted to 2-(2-methoxy-phenyl)-4,4-dimethyl-oxazoline and treatedwith an alkyl or aralkyl Grignard reagent to prepare the corresponding2-(2-alkyl phenyl)-4,4-dimethyl-oxazoline or 2-(2-aralkylphenyl)4,4-dimethyl-oxazoline (subsequent treatment of the 2-substitutedoxazoline with methyl iodide, reduction with sodium borohydride andsubsequent acid hydrolysis produces the corresponding 2-substitutedbenzaldehyde). The latter method is based upon methods disclosed byMeyers et at., J. Org. Chem., 43, 1372(1978). Similar methods forpreparing 2-substituted benzaldehydes are disclosed by Perchonock etal., J. Med. Chem., 28, 1145 (1985). In general, these methods employreagents which functionally displace substituents upon the aryl ring.

Methods for adding an ortho substituent to an aryl ring by rendering thearyl ring nucleophilic are also known. Org. Reactions, 26, 43-61 (1979)discloses that certain functional groups which contain nitrogenheteroatoms and are attached to phenyl rings can stabilize a phenyl ringtoward lithiation, preferably in the ortho position. The lithiated sitemay then be treated with a suitable electrophilic reagent to effectsubstitution. Functional groups which are reported therein to beparticularly effective for this purpose are mono- or di-alkyl amides,amines, N,N-dialkyl hydrazones, imidazolines and oxazolines. De Silva etat., Tetrahedron Lett., 5107 (1978), report an ortho-lithiation of abenzamide using sec-butyllithium and a diisopropyl amine, and Trecourtet al., J. Org. Chem., 53, 1367 (1988), report ortho-lithiation of2-methoxy-pyridine with methyllithium and a catalytic mount ofdiisopropylamine. Arylcarbimines, however, are reported to have limitedsynthetic utility due to their tendency to suffer from reaction at theazomethine linkage and alpha-deprotonation. See Org. Reactions, 26,57-58 (1979). Zeigler et at., J. Org. Chem., 41, 1564 (1976) report thatarylcarbimines may be induced to undergo ortho-lithiation if an adjacentether substituent is present.

In addition, it has been reported that methyl groups can be lithiated iflocated in the ortho position of benzamides, 2-phenyl imidazolines and2-phenyl oxazolines. Thus, Watanabe et al., J. Org. Chem., 49, 742(1984) report chain extension via an ortho-toluamide in the synthesis ofisocoumarins; Gschwend, et al., J. Org. Chem., 40, 2008 (1975), reportbenzylic chain extension via lithiation of 2-(o-tolyl)oxazolines; andHoulihan, U.S. Pat. No. 4,100,165, reports condensation of a dilithiated2-(o-tolyl)imidazoline with esters and acyl halides.

Current methods for the synthesis of the 2-substituted benzaldehydes ofthis invention employ expensive reagents or multiple process steps whichmake them unattractive for commercial preparation of 2-substitutedbenzaldehydes. There is therefore a need for an efficient alternativemethod for the preparation of 2-substituted benzaldehydes.

SUMMARY OF THE INVENTION

It is an object of this invention to provide a new and efficient processfor the preparation of compounds of formula (Ib): ##STR3## wherein:

R₁ is CH₂ CH₂ --(L₁)_(p) --(CH₂)_(q) --(L₂)_(r) --CH₂ --(T)_(s) --Z;

L₁ and L₂ are independently CH₂ CH₂, CH═CH or C.tbd.C;

q is 0to 8;

p, r and s are independently 0 or 1;

T is O, S, CH₂, CH═CH, C.tbd.C; and

Z is C₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl,thienyl, cyclohexyl or phenyl optionally mono substituted with CF₃, C₁₋₄alkyl, C₁₋₄ alkoxy, methylthio, or trifluoromethylthio; and

R₂ and A are independently H, CF₃, C₁₋₄ alkyl, F, Cl, Br or I.

One feature of this invention is a process for preparing a compound ofthe formula: ##STR4## wherein A, R₁, R₂, L₁, L₂, q, p, r, s, T and Z areas defined above for formula (Ib), which comprises reacting a compoundof the formula: ##STR5## wherein:

R₂ and A are as defined above for formula (Ib);

R₃ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, (CH₂)_(t) phenyl or N(R')₂ ;

R' is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(t) phenyl; and

t is 0 or 1;

with a base and a compound of the formula:

    X--CH.sub.2 --(L.sub.1).sub.p --(CH.sub.2).sub.q --(L.sub.2).sub.r --CH.sub.2 --(T).sub.s --Z                                (IV)

wherein:

L₁, L₂, p, q, r, s, T and Z are as defined above for formula (Ib), and Xis a displaceable group;

and treating the product thereof with acid.

Another feature of this invention is a novel intermediate according toformula (II): ##STR6## wherein:

R₁, R₂ and A are as defined for formula (Ib);

R₃ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, (CH₂)_(t) phenyl or N(R')₂ ;

R' is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(t) phenyl; and

t is 0 or 1.

Another feature of this invention is a process for the preparation ofthe novel intermediate of formula (II), which comprises reacting acompound of the formula (III): ##STR7## wherein A, R₂ and R₃ are asdefined for formula (II); with a base and a compound of the formula(IV):

    X--CH.sub.2 --(L.sub.1).sub.p --(CH.sub.2).sub.q --(L.sub.2).sub.r --CH.sub.2 --(T).sub.s --Z                                (IV)

wherein, L₁, L₂, p, q, r, s, T and Z are as defined above for formula(Ib); and

X is a displaceable group.

Yet another feature of this invention is an improved process forpreparing a compound of the formula (II), which comprises adding acatalytic amount of an organic amine to the reaction mixture prior toaddition of the base.

Still another feature of this invention is an improved process forpreparing a compound of the formula (II), which comprises adding asodium or potassium alkoxide to the reaction mixture.

Another feature of this invention is an improved process for preparing acompound of the formula (II), which comprises conducting the reactionwithin a specified temperature range.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses useful intermediates and a process forthe preparation of compounds of formula (Ib): ##STR8## wherein:

R₁ is CH₂ CH₂ --(L₁)_(p) --(CH₂)_(q) --(L₂)_(r) CH₂ --(T)_(s) --Z;

L₁ and L₂ are independently CH₂ CH₂, CH═CH or C.tbd.C;

q is 0 to 8;

p, r and s are independently 0 or 1;

T is O, S, CH₂, CH═CH, C.tbd.C; and

Z is C₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl,thienyl, cyclohexyl or phenyl optionally mono substituted with CF₃, C₁₋₄alkyl, C₁₋₄ alkoxy, methylthio, or trifluoromethylthio; and

R₂ and A are independently H, CF₃, C₁₋₄ alkyl, F, Cl, Br or I, whichcomprises reacting a compound of the formula: ##STR9## wherein:

R₂ and A are as defined above;

R₃ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, (CH₂)_(t) phenyl or N(R')₂ ;

R' is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(t) phenyl; and

t is 0 or 1;

with a base and a compound of the formula:

    X--CH.sub.2 --(L.sub.1).sub.p --(CH.sub.2).sub.q --(L.sub.2).sub.r --CH.sub.2 --(T).sub.s --Z                                (IV)

wherein:

L₁, L₂, p, q, r, s, T and Z are as defined above; and

X is a displaceable group;

and treating the product thereof with acid.

Accordingly, this invention discloses novel intermediates according toformula (II): ##STR10## wherein:

R₁ is CH₂ CH₂ --(L₁)_(p) --(CH₂)_(q) --(L₂)_(r) --CH₂ --(T)_(s) --Z;

L₁ and L₂ are independently CH₂ CH₂, CH═CH or C.tbd.C;

q is 0to 8;

p, r and s are independently 0 or 1;

T is O, S, CH₂, CH═CH, C.tbd.C; and

Z is C₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl,thienyl, cyclohexyl or phenyl optionally mono substituted with CF₃, C₁₋₄alkyl, C₁₋₄ alkoxy, methylthio, or trifluoromethylthio;

R₂ and A are independently H, CF₃, C₁₋₄ alkyl, F, Cl, Br or I;

R₃ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, (CH₂)_(t) phenyl or N(R')₂ ;

R' is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(t) phenyl; and

t is 0 or 1.

Suitably Z is phenyl and L₁ and L₂ are CH₂ CH₂.

Suitably R₃ is t-butyl.

Suitably p, r and s are 1.

Suitably q is 0-2.

Suitably T is CH₂ or C.tbd.C.

A preferred compound isN-[2-(8-phenyloctyl)phenyl)-methylene]-1,1-dimethylethanamine.

The novel intermediates of formula (II) are prepared by a process whichcomprises reacting a compound of formula (III): ##STR11## wherein:

R₂ and A are independently H, CF₃, C₁₋₄ alkyl, F, Cl, Br or I;

R₃ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, (CH₂)_(t) phenyl or N(R')₂ ;

R' is alkyl, cycloalkyl or (CH₂)_(t) phenyl; and

t is 0or 1;

with a base and a compound of the formula (IV):

    X--CH.sub.2 --(L.sub.1).sub.p --(CH.sub.2).sub.q --(L.sub.2).sub.r --CH.sub.2 --(T).sub.s --Z                                (IV)

wherein:

L₁ and L₂ are independently CH₂ CH₂, CH═CH or C.tbd.C;

q is 0to 8;

p, r and s are independently 0 or 1;

T is O, S, CH₂, CH═CH or C.tbd.C; and

Z is C₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl,thienyl, cyclohexyl or phenyl optionally mono substituted with CF₃, C₁₋₄alkyl, C₁₋₄ alkoxy, methylthio or trifluoromethylthio; and

X is a displaceable group.

In a preferred embodiment, this invention discloses a process forpreparing a compound of formula (Ib) which comprises reacting a compoundof formula (III) with a base and a compound of formula (IV) and treatingthe reaction mixture with acid. Thus, in the preferred embodiment, theoverall conversion is accomplished in a single reaction vessel withoutisolation of the intermediate product. This process utilizes readilyavailable materials and proceeds in efficient yield in a minimum numberof process steps.

Compounds of formula (III) are hydrazones and imines, or Schiff bases,and are generally prepared by any means common to the art for preparingsuch compounds. One method for preparing the imines comprises reacting acompound of formula (V): ##STR12## with an amine or a hydrazine of theformula, R₃ --NH₂. Such reactions are normally conducted by admixing thereactants in a non-aqueous solvent and optionally heating the tworeactants. Dehydrating agents may be used to drive the reaction towardsproduct if necessary. Common dehydrating agents are, for instance,molecular sieves or magnesium sulfate. Alternatively, dehydration may beeffected by azeotroping the water produced by the reaction from anappropriate solvent, such as benzene or toluene. The group R₃ is C₁₋₆alkyl, C₃₋₆ cycloalkyl, benzyl, phenyl or N(R')₂. Cyclohexylamine,t-butyl amine, aniline and N,N-dimethyl hydrazine are suitable reagents.t-Butyl amine is preferred.

The electrophile, given by formula (IV), is prepared by conventionalmethods, such as those disclosed in U.S. Pat. No. 4,820,719, U.S. Pat.No. 4,874,792, EPA 0 296 732 and Perchonock et al., J. Med. Chem., 28,1145 (1985) which are incorporated herein by reference. The X moiety ofthe electrophile represents a displaceable group, which may be any groupcapable of being displaced by the carbon nucleophile prepared from thecompound of formula (III). A large number of displaceable groups aresuitable, such as alkyl and aryl sulfonates, alkyl and aralkyl acetates,benzoates and halogens. Representative of the class are Cl, Br, I, R₄SO₃ and R₄ CO₂, wherein R₄ is C₁₋₄ alkyl, optionally substituted by 1-5fluorine atoms, or phenyl, optionally substituted by one or two halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy or nitro groups. Representative displaceablegroups are toluenesulfonate, bromobenzenesulfonate,nitrobenzene-sulfonate, methanesulfonate, trifluoromethanesulfonate,acetate, chloroacetate, trifluoroacetate, benzoate, bromobenzoate,chlorobenzoate, nitrobenzoate, chloro, bromo and iodo. Chloro and bromoare preferred. Chloro is especially preferred.

In general, the X group of the compounds of formula (IV), if not presentin the precursor, is prepared from the corresponding alcohol by reactionwith an appropriate acyl halide, anhydride, sulfonyl halide orappropriate halogenating agent. Typical of such reagents aretoluenesulfonyl chloride, bromobenzenesulfonyl chloride,nitrobenzenesulfonyl chloride, methanesulfonyl chloride, acetylchloride, chloroacetyl chloride, trifluoroacetic anhydride, benzoylchloride, bromobenzoyl chloride, chlorobenzoyl chloride, nitrobenzoylchloride, oxallyl chloride or bromide, hydrochloric acid, hydrobromicacid, hydroiodic acid, phosphorous tribromide, phosphorous trichloride,phosphorus oxychloride and carbon tetrabromide with triphenyl phosphine.Compounds of the formula HO--CH₂ --(L₁)_(p) --(CH₂)_(q) --(L₂)_(r) --CH₂--(T)_(s) --Z, wherein T is CH₂, L₁ or L₂ are CH₂ CH₂, and Z is C₁₋₄alkyl or phenyl are generally available commercially. Compounds whereinT is O, S or C.tbd.C, may be prepared by reacting the compound H-T-Zwith a compound of the structure X--CH₂ --(L₁)_(p) --(CH₂)_(q)--(L₂)_(r) --CH₂ --X, wherein X, L₁, L₂, T, p, q and r are as definedabove, in the presence of an appropriate base. Compounds wherein T isCH═CH may be prepared by semi-hydrogenation of compounds wherein T isC.tbd.C, such as with Lindlar's catalyst or 5% palladium on bariumsulfate and hydrogen. Hydrogenation with a palladium catalyst, such as5% palladium on carbon, yields the compound wherein T is CH₂. When L₁ orL₂ are C.tbd.C or CH═CH the resulting product may be reduced at asubsequent time to yield a product wherein L₁ or L₂ are CH═CH or CH₂CH₂. For example, 1-bromo-7-phenylheptane is prepared from1,5-dibromopentane and phenylacetylene in the presence of n-butyllithium, followed by reduction with hydrogen over a palladium catalyst.In an alternate example, 1-bromo or 1-chloro-7-phenylheptane may beprepared via a copper mediated coupling of benzyl magnesium halide with1,6 dibromohexane or 1-bromo-6-chlorohexane.

Alkylation of the carbimine of formula (III) is initiated by reacting acompound of formula (III) with a strong base to deprotonate the orthomethyl group. Since the metallated intermediate is reactive with water,the activation reaction is suitably carried out in an inert, dryatmosphere, such as nitrogen or argon, although dry air is sufficient.

The activation reaction is carried out in an aprotic solvent. Suitablesolvents for this reaction are common aliphatic or aromatic hydrocarbonsolvents which are unreactive to strong bases. Representative of suchsolvents are diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane,toluene, benzene, pentane, hexane and petroleum ethers, and mixturesthereof. Diethyl ether, dioxane and tetrahydrofuran are preferred.Tetrahydrofuran is especially preferred.

A base of sufficient strength to deprotonate the ortho methyl group isrequired. Any base capable of effecting such deprotonation withoutcausing appreciable side reactions is suitable. Typical of such basesare an alkali metal alkyl, an alkali metal amine (e.g., a salt of anorganic or inorganic amine), or an alkali metal aryl. Representative ofsuch bases are n-butyl lithium, sec-butyl lithium, methyl lithium,phenyl lithium, lithium diisopropylamide, lithium tetramethylpiperidide,lithium diethylamide or lithium amide, or the corresponding sodium orpotassium salt of any of these species. Alkyl lithium reagents areespecially suitable. n-Butyl lithium, lithium tetramethylpiperidide andlithium diisopropylamide are preferred. It is also within thecontemplation of this invention that the metal of the base initiallyused may be exchanged for another metal, for instance another alkalimetal, copper, magnesium or zinc. It is often helpful to use a slightmolar excess of base, such as 1% to 25%, to ensure complete metallation.About one molar equivalent is normally satisfactory. It will be apparentto one skilled in the an that certain of these bases, such as alkalimetal alkyl or aryl, may be incompatible with a halogen substituent inthe carbimine, and that other bases, such as lithium diisopropylamidewould be more suitable.

The reaction of a compound of formula (III) with the base is carded outby admixing the two reactants. The reaction should be carried out at atemperature sufficient to cause the base to deprotonate the ortho methylgroup, yet not so high as to cause adverse side reactions. Thus, theoptimum temperature will be dependent upon the base used and the iminereactant. If the base is a lithium dialkyl amide, typically the reactionis carded out between about -20° C. and 60° C.; suitably, the reactionis carded out between about -10° C. and 40° C.

It has been found that surprisingly improved yields are obtained whenthe reaction is run using an organolithium base at between about 15° C.to about 35° C. Typically, when strong bases are reacted with compoundswhich possess a moiety which is susceptible to nucleophilic attack, suchas a carbimine function, the reactions are conducted at temperatures ofabout 0° C. and lower. These lower temperatures are believed to preventundesirable side reactions, such as nucleophilic attack upon the labilecarbimine functionality by the base itself or by the anion created bythe action of the base. Unexpectedly, with certain bases, such asn-butyllithium optionally with a catalytic amount of diisopropyl amineor dicyclohexylamine, side reactions are minimized and yields areincreased by adding the base to the carbimine at about 15° C. to about35° C. Conducting the reaction between about 20° C. to about 30° C. isespecially suitable. Temperatures above 55° C. generally result in anenhancement of undesirable side reactions.

The electrophile, X--CH₂ --(L₁)_(p) --(CH₂)_(q) --(L₂)_(r) --CH₂--(T)_(s) --Z, is typically added upon completion of the metallationreaction. Although the electrophile may be added neat, it isconveniently added in a solvent such as that which has been used to formthe metallated intermediate. The reaction is then allowed to stir forabout 15 min to about 24 h.

If the imine is to be isolated, the reaction solution is diluted with anappropriate solvent, washed with water and concentrated in vacuo to anoil. If a purified product is desired, the product is purified bydistillation, or, if appropriate, by crystallization.

Conversion of a compound of formula (II) to a benzaldehyde isaccomplished by stirring the imine with any acid of sufficient strengthto cause hydrolysis of the C═N bond. Within the context of thisinvention mineral acids, organic acids and the like are considered to besufficiently strong acids. For example, methanesulfonic acid,toluenesulfonic acid, trifluoroacetic acid, benzoic acid, acetic acid,hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, nitric acid and phosphoric acid, are all suitable.Mineral acids are preferred. Hydrochloric add is especially preferred.

In the preferred process, the reaction mixture containing the product(II) is hydrolyzed directly by the addition of acid to the reactionmixture. Generally, the reaction mixture is added to a cooled solutionof the acid and thereafter allowed to warm to room temperature. Thereaction mixture may be monitored for formation of the desiredbenzaldehyde, such as by analytical chromatography, but typically thereaction is stirred from about 1 h to about 24 h. The product is thenisolated by conventional techniques, such as extractive workup.

An improved process for preparing a compound of the formula (II),comprises adding a catalytic amount of an organic amine to the reactionmixture prior to addition of the base, particularly when an alkyllithium reagent is used as the base. Higher yields are obtained when acatalytic amount of an organic amine is used than when the amine isabsent or when a full molar equivalent of the amine is employed.Suitably the organic amine is a secondary amine. Representative aminesare diethylamine, diisopropylamine, dicyclohexylamine, piperidine,2,6-dimethylpiperidine, and 2,2,6,6-tetramethylpiperidine.Diisopropylamine, dicyclohexylamine, and 2,2,6,6-tetramethylpiperidineare especially suitable. The catalytic amount may be from about 0.01 toabout 0.3 molar equivalents of organic amine relative to the carbimine.About 0.01 to about 0.15 molar equivalents is suitable. About 0.01 to0.1 molar equivalents is typical, depending on the amine used. Forinstance, about 0.01 to about 0.05 equivalents are useful fordiisopropylamine and 2,2,6,6-tetramethylpiperidine.

Still another feature of this invention is an improved process forpreparing a compound of the formula (II), which comprises preparing asodium or potassium salt of the carbimine of formula (III) and reactingthe product with a compound of the formula (IV). For instance, the2-methyl-phenyl carbimine of formula (III) may be treated with a basesuch as n-butyllithinm or lithium diisopropylamide, to form the lithiumsalt, and further treated with a sodium or potassium base or salt toform the desired salt by a metal exchange reaction. Sodium or potassiumalkoxide, or sodium or potassium trifluoroacetate are representativebases/salts. Reaction of the carbimine salt with a compound of formula(IV), such as 7-phenylheptylchloride, effects alkylation at lowertemperatures, and with fewer side reactions, than obtained With thecomparable lithium salt of the carbimine. Use of the potassium salt isespecially suitable.

The examples which follow illustrate how to make and use the compoundsand processes which constitute this invention.

EXAMPLES

The nomenclature and abbreviations common to the chemical an are used inthe examples. Unless otherwise noted, reagents were obtained fromcommercial suppliers and were used without further purification.Tetrahydrofuran, if used as a reaction solvent, was dried over 4Åmolecular sieves if necessary. All other solvents were obtained fromcommercial suppliers as Reagent grade and were used without furtherpurification. All non-aqueous reactions were performed under anatmosphere of dry nitrogen. Melting points were taken on a Thomas-Hoovercapillary melting point apparatus and are uncorrected. Liquidchromatography was conducted on a Whatman Partisil® 5 ODS 3 RAC II. Gaschromatographic analysis was performed on a DB-1 30 m×0.53 mm capillarycolumn. IR spectra were recorded on a Perkin-Elmer Model 283 infraredspectrophotometer. FT-IR spectra were obtained on a Nicolet 6000 FTinfrared spectrometer. Combustion analyses were run on a Perkin-Elmer240 C elemental analyzer. Unless otherwise indicated all ¹ H-NMR (protonmagnetic resonance) spectra were obtained at 400 MHz, using a BrukerInstruments WM 400 spectrometer in deuterochloroform solution. ¹³ C-NMRspectra were obtained at 100 MHz. Chemical shifts are reported in ppm(δ) downfield from tetramethylsilane. Annotations to ¹ H-NMR are asfollows: s, singlet; d, doublet; t, triplet; br, broad; m, multiplet; J,coupling constant in Hertz.

Example 1

Preparation of 1-bromo-7-phenylheptane

To a stirred solution of 1500 mL (0.15 mol) of 0.1M Li₂ CuCl₄ and1,6-dibromohexane (456.8 g, 1.87 mol, 1.25 eq) in tetrahydrofuran, at -5to 0° C., was added a solution of benzyl magnesium chloride (750 mL, 2Min tetrahydrofuran, 1.5 mol) over a 90 min period. The reaction mixturewas stirred at 0° C. for 90 min, then quenched carefully with 2.0 L ofsaturated aqueous ammonium chloride. The internal reaction temperaturewas kept below 20° C. during the quench. The mixture was stirred for 1 hat room temperature and the layers separated. The organic layer waswashed with 20% aqueous sodium chloride (4×500 mL). The organic layerwas dried (magnesium sulfate), filtered, and concentrated in vacuo at45°-50° C. to an amber oil. Purification by fractional vacuumdistillation through a 12-inch vacuum-jacketed Vigreux column gave thedesired product as a colorless oil (198.2 g, 52%). An analytical samplewas prepared by redistillation: bp 123°-124° C. (1.5 mm Hg); FT-IR (neatfilm) 3100-3000, 3000-2800, 2000-1700, 1604, 1496, 748, 699, 644 cm⁻¹ ;¹ H NMR (CDCl₃, 400 MHz) δ 7.29-7.16 (m, 5 H), 3.40 (t, 2 H), 2.60 (t, 2H), 1.88-1.81 (m, 2 H), 1.63-1.60 (m, 2 1.32 (m, 6 H); ¹³ C NMR (CDCl₃,100 MHz) δ 142.7, 128.4, 128.2, 125.6, 35.9, 34.0, 32.8, 31.4, 29.1,28.6, 28.1. Anal. Calcd for C₁₃ H₁₉ Br: C, 61.19; H, 7.50; Br, 31.31.Found: C, 61.25; H, 7.59; Br, 31.47.

Example 2

Preparation of 7-chloro-1-phenyl heptane

a) 1-bromo-6-chlorohexane,

A mixture of 1,6-hexanediol (30 kg, 254 mol), 48% hydrobromic acid (51.0kg, 302 mol) and toluene was heated to reflux. Water (34.5 kg) wasremoved under azeotropic conditions. When distillation ceased themixture was cooled to 20° C. and extracted with a solution ofconcentrated hydrochloric acid (69.9 kg) and water (60 L). The phaseswere separated and the organic phase dried by reheating and removingwater by azeotropic distillation. The mixture was cooled to 65° C. anddimethylformamide (1.11 kg) was added. Thionyl chloride (31.41 kg, 264mol) was added over 45 min while maintaining the temperature between65°-68° C. The mixture was heated to 109° C. over 1.25 h and cooled to20° C. It was then washed successively with 20% sodium hydroxidesolution (100 L) and water (2×150 L, 1×100 L). Toluene (400 L) wasremoved under vacuum to yield the bromochlorohexane as a toluenesolution (85.5 kg, 55% w/w by assay, 93% yield).

b) 7-chloro-1-phenylheptane

A solution of lithium tetrachlorocuprate [THF 33 L, lithium chloride(0.87 kg, 19.3 mol), cupric chloride (1.4 kg, 10.4 mol)] was added to asolution of benzylmagnesium chloride (160 L of 1.86M, 298 mol) intetrahydrofuran at 15° C., and the mixture stirred for 30 min.Bromochlorohexane in toluene (85.5 kg of solution, 55% w/w by assay,47.1 kg, 236 mol) was added over 3 h while maintaining the temperaturebetween 15°-20° C. Stirring was continued for a further 1.25 h. 10%Ammonium chloride solution (263 L) was added over 1 h, maintaining thetemperature below 30° C. The phases were separated and the organic phasefurther washed with ammonium chloride solution (170 L) and 20% sodiumchloride solution (3×197 L). The organic solution was concentrated undervacuum to leave an oil (56.8 kg, 77% pure by HPLC assay, 88% correctedyield), which was distilled (b.p. 129°-132° C., 2 mbar) to yield thetitle compound (70%, 99% pure by GC assay).

Example 3

Preparation of N-[(2-methylphenyl)methylene]-1,1-dimethyl-ethanamine

A stirred solution of o-tolualdehyde (25 g, 0.21 mol), and t-butylamine(27.75 g, 0.38 mol) in toluene (250 mL) was refluxed under standardDean-Stark conditions for 20 h. The solution was evaporated to an oilwhich was vacuum distilled (bp 70°-73° C., 0.6 mm Hg) to afford 33.9 g(93%) of product: IR (neat) 2980, 1645, 1605, 1460, 1375, 1210, 960, 910cm⁻¹ ; ¹ H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1 H), 7.86-7.83 (m, 1 H),7.25-7.11 (m, 3 H), 2.46 (s, 3 H), 1.30 (s, 9 H); ¹³ C NMR (CDCl₃, 100MHz) δ 153.7, 137.1, 135.1, 130.5, 129.6, 127.1, 126.4, 57.5, 29.8,19.2; GC RT 7.6 min (DB-1, 30 m×0.53 mm, program: 100° C. for 5 min,100°-260° C. at 15° C./min, hold at 260° C. for 12 min).

Example 4

Preparation of 2-methylbenzaldehyde dimethyl hydrazone

A stirred solution of o-tolualdehyde (25.0 g, 0.21 mol), and1,1-dimethyl hydrazine (25.2 g, 0.42 mol) was refluxed in toluene (200mL) for 24 h. The solution was concentrated in vacuo and the residualoil was vacuum distilled (51°-60° C., 0.2 mm Hg) to afford the tidedproduct (31.98 g, 94%): IR (neat) 2950, 2850, 1580, 1550, 1455, 1025,745 cm-1; ¹ H NMR (CDCl₃, 400 MHz) δ 7.8-7.6 (m, 1H), 7.4-7.3 (m, 1H),7.1-6.9 (m, 3H), 2.9 (s, 6H), 2.4 (s, 3H).

Example 5

Preparation ofN-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethanamine

To a stirred solution of diisopropylamine (29.14 g,0.289 mol) intetrahydrofuran (450 mL) cooled to -5° C. was added n-butyllithium(2.5M, 114.3 mL, 0.286 mol) at a rate which maintained the solutiontemperature below 10° C. After the addition was complete, the solutionwas stirred 15 min with cooling. To this solution was addedN-[(2-methylphenyl)-methylene]-1,1-dimethylethanamine (50.0 g, 0.286mol) in tetrahydrofuran (65.0 mL) at such a rate as to keep the reactiontemperature below 5° C. The reaction was stirred for 15 min with coolingthen 1-bromo-7-phenylheptane (72.9 g, 0.286 mol) in tetrahydrofuran (75mL) was quickly added. The reaction mixture was stirred for 1 h withcooling then allowed to warm to room temperature and stirred for anadditional 14 h. The reaction mixture was assayed by gas chromatographyfor product imine (RT 19.8 min., DB-1, 30 m×0.53 mm, program, 100° C.for 5 min, 100°-260° C. at 15° C./min, hold at 260° C. for 12 min.). Theproduct was isolated by dilution of the reaction mixture with water andmethylene chloride, quickly washing the organic mixture with water, andconcentrating the solution to an oil. The oil was purified bydistillation.

Example 6

Preparation ofN-[(2-(8-phenyloctyl)phenyl)-methylene]-1,1-dimethylethanamine

A stirred solution of 2-(8-phenyloctyl)benzaldehyde (10 g, 0.034 mol),and t-butylamine (4.96 g, 0.068 mol) in toluene (100 mL) was refluxedunder standard Dean-Stark conditions for 16 h. The solution wasevaporated to an oil which was vacuum distilled (bp 260° C., 0.15 mm Hg)to afford the titled product (11.1 g, 94%): GC RT 19.8 min (DB-1, 30m×0.53 mm, program, 100° C. for 5 min, 100°-260° C. at 15° C./min, holdat 260° C. for 12 min.); ¹ H NMR (CDCl₃, 400 MHz) δ 8.58 (s, 1H), 7.86(d, J=7.5 Hz, 1H), 7.29-7.13 (m, 8H), 2.79 (t, J=7.5 Hz, 2H), 2.58 (t,J=7.5 Hz, 2H), 1.59-1.51 (m, 12H), 1.30 (s, 9H).

Example 7

Preparation of 2-(8-phenyloctyl)benzaldehyde

Via hydrolysis ofN-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethanamine

To a solution ofN-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethanamine (0.51 g,0.0146 mol) in tetrahydrofuran (5 mL) was added 10% aqueous hydrochloricacid (5 mL) and the mixture stirred for 15 h at room temperature.Methylene chloride (10 mL) and water (10 mL) were added and the layersseparated. The aqueous layer was extracted with methylene chloride (1×15mL) and the combined organics were dried (magnesium sulfate), filteredand concentrated in vacuo to an oil (0.405 g, 97.4% pure by HPLC assay,92% corrected yield): IR (neat) 2920, 2880, 1695, 1600, 1455 cm⁻¹ ; ¹ HNMR (CDCl₃, 400 MHz) δ 10.25 (s, 1 H), 7.80 (dd, 1 H, J=1.2 and 7.7 Hz),7.45 (m, 1 H), 7.33-7.13 (m, 7 H), 2.98 (t, 2 H, J=7.7 Hz), 2.58 (t, 2H, J=7.7 Hz), 1.58 (m, 4 H), 1.30 (m, 8H).

Example 8

Preparation of 2-(8-phenyloctyl)benzaldehyde

Using one mole equivalent of a nitrogenous base and1-bromo-7-phenylheptane

To a stirred solution of diisopmpylamine (29.14 g,0.289 mol) intetrahydrofuran (450 mL) cooled to -5° C. was added n-butyllithium(2.5M, 114.3 mL, 0.286 mol) at a rate which maintained the solutiontemperature below 10° C. After the addition was complete, the solutionwas stirred 15 min with cooling. To this solution was addedN-[(2-methylphenyl)-methylene]-1,1-dimethylethanamine (50.0 g, 0.286mol) in tetrahydrofuran (65.0 mL) at such a rate as to keep the reactiontemperature below 5° C. The reaction was stirred for 15 min with coolingthen 1-bromo-7-phenylheptane (72.9 g, 0.286 mol) in tetrahydrofuran (75mL) was quickly added. The reaction mixture was stirred for 1 h withcooling then allowed to warm to room temperature and stirred for anadditional 14 h. The reaction mixture was quenched with aqueous 10%hydrochloric acid solution, and was stirred for 1 h at 0° C., then atambient temperature for 14 h. The reaction mixture was poured intomethylene chloride (700 mL) and stirred for 5 min. The organic layer wasremoved, and the aqueous layer extracted with methylene chloride (2×700mL). The combined organic layers were washed with 10% hydrochloric acid(2×500 mL) and saturated brine (1×350 mL), then concentrated in vacuo toa golden oil. The crude product was passed through a Pope Still (100°C., 0.2 mm Hg) and the residue treated with hexane (400 mL) withstirring for 5 min. The solution was allowed to settle, and decanted.The hexane treatment was repeated an additional two times, and thecombined hexane washes were then filtered through a Celite® plug andconcentrated to a light yellow oil (72.5 g,92.4% pure by HPLC assay,82%corrected yield). For analytical purposes, a small sample was furtherpurified by Kugelrohr distillation (250° C., 0.1 mm Hg): IR (neat) 2910,1695, 1600, 1450, 1210, 1190 cm⁻¹ ;¹ H NMR (CDCl₃, 400 MHz) δ 10.25 (s,1 H), 7.80 (dd, 1 H, J=1.2 and 7.7 Hz), 7.45 (m, 1 H), 7.33-7.13 (m, 7H), 2.98 (t, 2 H, J=7.7 Hz), 2.58 (t, 2 H, J=7.7 Hz), 1.58 (m, 4 H),1.30 (m, 8 H); ¹³ C NMR (CDCl₃, 100 MHz) δ 192.2, 145.7, 142.8, 133.7,133.6, 131.3, 130.9, 128.3, 128.2, 126.3, 125.5, 35.9, 32.4, 32.4, 31.4,29.5, 29.4, 29.3, 29.2; HPLC RT 5.8 min (Whatman Partisil® 5 ODS 3 RACII, 4.6 mm I.D.×10 cm, 2 mL/min, 7:3 CH₃ CN:H₂ O, UV detection at 211nm).

Example 9

Preparation of 2-(8-phenyloctyl)benzaldehyde

Using two mole equivalents of imine and nitrogenous base and one moleequivalent of 1-chloro-7-phenylheptane

A solution of lithium diisopropylamide in THF (15.4 g, 0.024 mol) wasadded to THF (30 mL) and cooled to -10° C. under a nitrogen atmosphere.A solution of N-[(2-methylphenyl)-methylene]-1,1-dimethylethanamine(4.23 g, 0.024 mol) in THF (5 ml) was added and the mixture was stirredat -10° C. for 20 min. Phenylheptylchloride (2.77 g, 0.012 mol) in THF(5 ml) was added and the mixture was heated to 58° C. GC analysis showedno phenylheptylchloride remaining after 3 h. The mixture was cooled to0° C. and dilute HCl (50 mL) was added such that the temperature waskept below 25° C. The solution was reheated to 58° C. where it wasmaintained for 16 h. After cooling to 20° C., methylene chloride (100ml) was added and the phases were separated. The aqueous phase wasfurther extracted with methylene chloride (50 ml) and the combinedorganic phases washed with water (100 ml). After drying over magnesiumsulphate, filtering and evaporation of the solvent the product wasobtained as an oil weighing (6.96 g, 28.6% pure by HPLC assay, 57%corrected yield).

Using the above conditions, but stirring the reaction mixture at ambienttemperature for 20 h instead of refluxing for 3 h, a corrected yield of59% was obtained.

Using the above conditions, but employing one molar equivalent of thecarbimine and amine base relative to the phenylheptylchloride, acorrected yield of 42% was obtained.

Example 10

Preparation of 2-(8-phenyloctyl)benzaldehyde

Exchanging potassium for lithium as basic counterion/using differentimines

a) N-[(2-methylphenyl)methylene]-1,1-dimethylethanamine (5.00 g, 29mmol) was added to a solution of lithium diisopropylamide [28.5 mmol;prepared from diisopropylamine (4.0 mL, 2.89 g, 29 mmol) and n-butyllithium (2.5M, 11.43 mL, 28.5 mmol)] in THF (50 mL) at -10° C. Afterstirring at this temperature for 75 min, a solution of potassiumt-butoxide (1.49M, 19.2 mL, 28.5 mmol) in THF was added. After a further15 min, 1-chloro-7-phenylheptane (3.77 g, 17.9 mmol) was added. Thereaction was allowed to warm to room temperature and stirred for 16 h.Hydrochloric acid (6M, 5 mL) was added and the mixture was refluxed for90 min. The aqueous layer was separated and extracted with hexane (2×200mL). The combined organic fractions were dried over sodium sulphate,filtered and the solvents removed by evaporation under reduced pressureto give an oil (7.44 g). Assay of this material showed it to contain 65%w/w phenyloctylbenzaldehyde (4.84 g, 16.5 mmol, 92%).

b) Using the procedure of (a), except substitutingN-[(2-methylphenyl)methylene]-isopropylamine andN-[(2-methylphenyl)methylene]-n-butylamine, gave the following results:

    ______________________________________    R.sub.3          ratio    imine substituent                     imine:PHC Yield (%)    ______________________________________    i)     t-Bu          1.6:1     92    ii)    i-Pr          2.0:1     31    iii)   n-Bu          2.0:1     ˜10    ______________________________________

Example 11

Preparation of 2-(8-phenyloctyl)benzaldehyde

Use of a catalytic mount of a nitrogen base/comparison of differentelectrophiles

a) phenylheptylbromide/phenylheptyliodide

i.) To a solution ofN-[(2-methylphenyl)methylene]-1,1-dimethylethanamine (5.0 g, 0.03 mol)and N,N,N',N'-tetramethylethylene diamine (3.31 g, 0.03 mol) intetrahydrofuran (40 mL), n-butyl lithium (2.5M, 11.4 mL, 0.03 mol) at 0°C. was slowly added. The solution was stirred for an additional 30 minfollowed by the quick addition of 1-bromo-7-phenylheptane (7.28 g, 0.03mol) in tetrahydrofuran (10 mL). The reaction mixture was allowed towarm to room temperature and stirring was continued for 15 h. Thereaction mixture was quenched with 10% aqueous hydrochloric acid (50 mL)and stirred for 30 min. The layers were separated, methylene chloride(50 mL) was added to the organic layer and the organics were washed withsaturated brine solution (50 mL). The organics were then dried(magnesium sulfate), and concentrated to an oil to yield2-(8-phenyloctyl)benzaldehyde (3.8 g, 45%): IR (neat film) 2920, 2880,1695, 1600, 1455 cm⁻¹ ; ¹ H NMR (CDCl₃, 400 MHz) δ 10.25 (s, 1 H), 7.80(dd, 1 H, J=1.2 and 7.7 Hz), 7.45 (m, 1 H), 7.33-7.13 (m, 7 H), 2.98 (t,2 H, J=7.7 Hz), 2.58 (t, 2 H, J=7.7 Hz), 1.58 (m, 4 H), 1.30 (m, 8 H).

ii) Using the procedure of (a)(i), except substituting1-iodo-7-phenylheptane for 1-bromo-7-phenylheptane,2-(8-phenyloctyl)benzaldehyde was prepared in 34% yield.

b) 1-bromo-7-phenylheptane/1-chloro-7-phenylheptane

i) A solution of N-[(2-methylphenyl)methylene]-1,1-dimethylethanamine(2.8 g, 0.016 mol) and 2,2,6,6-tetramethylpiperidine (0.23 g, 0.0016mol) in tetrahydrofuran (10 mL) was cooled to -5° C. To this was addedn-BuLi (1.6M, 10 mL, 0.016 mol) over 40 min maintaining the temperatureat -5° C. A solution of 1-bromo-7-phenylheptane (3.4 g, 0.0133 mol) intetrahydrofuran (5 mL) was added quickly at -5° C. The temperaturequickly rose to 40° C. and after cooling to ambient temperature themixture was stirred for 1 h. The mixture was quenched by the addition ofdilute hydrochloric acid and stirred at ambient temperature for 16 h.The product was isolated in the usual manner (5.0 g, 75% pure, 96%corrected yield).

ii) Using the procedure of (b)(i), except substituting1-chloro-7-phenylheptane for 1-bromo-7-phenylheptane, phenyloctylbenzaldehyde was prepared in 87% corrected yield.

Example 12

Preparation of 2-(8-phenyloctyl)benzaldehyde

Effect of changing the temperature at which anion is formed for variousnitrogen bases.

a) A stirred solution ofN-[(2-methylphenyl)methylene]-1,1-dimethylethanamine (11.2 g, 0.064 mol)and 2,2,6,6-tetra-methylpiperidine (0.9 g, 0.0064 mol) intetrahydrofuran (40 mL) was cooled to -5° C. To this was added n-BuLi(1.6M, 40 mL, 0.064 mol) over 60 min from a syringe pump such that thetemperature was maintained below 0° C. The mixture was stirred for 30min and 1-chloro-7-phenylheptane (11.23 g, 0.053 mol) in tetrahydrofuran(20 mL) quickly added. The reaction mixture was heated at 50°-55° C. for2 h. The reaction mixture was cooled to 40° C. and quenched by the slowaddition of dilute hydrochloric acid (100 mL of acid diluted with 300 mLof water). Hydrolysis was completed by heating the mixture at 50°-60° C.for 2.5 h. The mixture was cooled to ambient temperature and the organicphase separated. The aqueous phase was extracted with hexane (100 mL)and the combined organic extracts washed with water (100 mL). Theextracts were dried over magnesium sulphate and after filtering andwashing the filter cake with hexane the organic solution wasconcentrated under vacuum to give 2-(8-phenyloctyl)benzaldehyde as anoil (14.5 g, 69.3% pure by HPLC assay, 87% corrected yield).

b) To a stirred solution ofN-[(2-methylphenyl)methylene]-1,1-dimethylethanamine (21.0 g, 0.12 mol)in tetrahydrofuran (75 mL), n-BuLi (1.54M, 78 mL, 0.12 mol) was addedover 1 h such that the temperature was maintained between 20°-30° C.with cooling. The mixture was stirred for 30 min and1-chloro-7-phenylheptane (21.05 g, 0.1 mol) in tetrahydrofuran (40 mL)was added quickly. The mixture was heated at 50° C. for 3 h and quenchedby the slow addition of dilute hydrochloric acid. Hydrolysis wascompleted by heating the mixture at 50°-60° C. for 2.5 h. The mixturewas cooled to ambient temperature and the organic phase separated. Theaqueous phase was extracted with hexane, and the combined organicextracts were washed with water. The extracts were dried over magnesiumsulphate and, after filtering and washing the filter cake with hexane,the organic solution was concentrated under vacuum to give2-(8-phenyloctyl)benzaldehyde as an oil (34.56 g, 65.3% pure by HPLCassay, 77% corrected yield).

c) Using the same procedure as in (a) or (b), except varying thenitrogen base and the temperature at which the anion was formed, thefollowing results were obtained:

    ______________________________________               Anion     solution impurity                                         profile    Amine      temp. (°C.)                         yield (%)                                  (% PHE*)                                         (% PHC**)    ______________________________________    i)   (i-Pr).sub.2 NH                   -5        55     7.2    17.3    ii)  (i-Pr).sub.2 NH                   25        94     1.8    0    iii) DCA.sup.†                   -5        48     8.6    14.9    iv)  DCA.sup.†                   25        83     1.7    0.1    v)   TMP.sup.††                   -5        87     0.6    0.4    vi)  TMP.sup.††                   25        89     0.7    0.7    vii) --         0        45     ND     ND    viii)         --        25        77     ND     ND    ______________________________________     DCA.sup.† = dicyclohexylamine     TMP.sup.†† = tetramethylpiperidine     PHE* = phenylheptene     PHC** = phenylheptylchloride

d) Using the procedure of (a) or (b), except substituting1-bromo-7-phenylheptane, the following results were obtained

    ______________________________________               Anion     solution impurity                                         profile    Amine      temp. (°C.)                         yield (%)                                  (% PHE*)                                         (% PHB***)    ______________________________________    i)   (i-Pr).sub.2 NH                    0        89     ND     ND    ii)  TMP       25        96     ND     ND    ii)  SS/1195/119    ______________________________________     PHB*** = phenylheptylbromide

Many variations of these examples will be apparent to one skilled in theart and this invention is not limited to these examples, but includesall variations encompassed by the claims which follow.

What is claimed is:
 1. A process for preparing a compound of theformula: ##STR13## wherein: R₁ is CH₂ CH₂ --(L₁)_(p) --(CH₂)_(q)--(L₂)_(r) --CH₂ --(T)_(s) --Z;L₁ and L₂ are independently CH₂ CH₂,CH═CH or C.tbd.C; q is 0 to 8; p, r and s arc independently 0 or 1; T isO, S, CH₂, CH═CH, C.tbd.C; and Z is C₁₋₄ alkyl, ethynyl,trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyloptionally mono substituted with CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylthio, or trifluoromethylthio; and R₂ and A are independently H,CF₃, C₁₋₄ alkyl, F, Cl, Br or I; which comprises reacting a compound ofthe formula: ##STR14## wherein: R₂ and A are as defined above; R₃ isC₁₋₆ alkyl, C₃₋₆ cycloalkyl, (CH₂)_(t) phenyl or N(R')₂ ; R' is C₁₋₆alkyl, C₃₋₆ cycloalkyl or (CH₂)_(t) phenyl; and t is 0or 1;with alithium alkyl or lithium amine base and a compound of the formula:

    X--CH.sub.2 --(L.sub.1).sub.p --(CH.sub.2).sub.q --(L.sub.2).sub.r --CH.sub.2 --(T).sub.s --Z                                (IV)

wherein: L₁, L₂, p, q, r, s, T and Z are as defined above; and X is adisplaceable group;and treating the product thereof with acid.
 2. Aprocess according to claim 1 in which the base is added to the compoundof formula (III) at about 15° C. to about 35° C. and the base is alithium alkyl or lithium diisopropyl amide.
 3. A process according toclaim 1 in which R₂ and A are H, R₃ is t-butyl, and X is bromo orchloro.
 4. A process according to claim 1 in which the acid is a mineralacid.
 5. A process according to claim 4 in which the acid ishydrochloric acid.
 6. A process for preparing 2-(8-Phenyloctyl)benzaldehyde in whichN-[(2-methylphenyl)methylene]-1,1-dimethylethanamine is reacted withn-butyllithium and a catalytic amount of an organic amine, and1-chloro-7-phenylheptane, and subsequently treated with hydrochloricacid.
 7. A process for preparing 2-(8-phenyloctyl)benzaldehyde in whichN-[(2-methylphenyl)methylene]-1,1-dimethylethanamine is reacted withlithium diisopropyl amide, potassium butoxide, and1-chloro-7-phenylheptane, and subsequently treated with hydrochloricacid.
 8. A process for preparing a compound of the formula: ##STR15##wherein: R₁ is CH₂ CH₂ --(L₁)_(p) --(CH₂)_(q) --(L₂)_(r) --CH₂ --(T)_(s)--Z;L₁ and L₂ are independently CH₂ CH₂, CH═CH or C.tbd.C; q is 0 to 8;p, r and s are independently 0 or 1; T is O, S, CH₂, CH═CH, C.tbd.C; andZ is C₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl,thienyl, cyclohexyl or phenyl optionally mono substituted with CF₃, C₁₋₄alkyl, C₁₋₄ alkoxy, methylthio, or trifluoromethylthio; R₂ and A areindependently H, CF₃, C₁₋₄ alkyl, F, Cl, Br or I; R₃ is C₁₋₆ alkyl, C₃₋₆cycloalkyl, (CH₂)_(t) phenyl or N(R')₂ ; R' is C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(t) phenyl; and t is 0 or 1;which comprises reactinga compound of the formula (III): ##STR16## wherein A, R₂ and R₃ are asdefined above; with a lithium alkyl or lithium amine base and a compoundof the formula (IV):

    X--CH.sub.2 --(L.sub.1).sub.p --(CH.sub.2).sub.q --(L.sub.2).sub.r --CH.sub.2 --(T).sub.s --Z                                (IV)

wherein: L₁, L₂, T, Z, p, q, r and s arc as defined above; and X is adisplaceable group.
 9. A process according to claim 8 in which the baseis a lithium alkyl.
 10. A process according to claim 8 in which the baseis lithium diisopropylamide or butyl lithium.
 11. A process according toclaim 9 in which a catalytic amount of an organic amine is present. 12.A process according to claim 11 in which the organic amine isdiisopropyl amine, 2,2,6,6-tetramethylpiperidine, or dicyclohexylamine,and the organic amine is present in an mount of about 0.01 to 0.15 moleequivalents of the compound of formula (III).
 13. A process according toclaim 9 in which the base and the compound of formula (III) are reactedat a temperature of about 15° C. to about 35° C.
 14. A process accordingto claim 10 in which a sodium or potassium alkoxide is added to thereaction mixture prior to the addition of the compound of formula (IV).15. A process according to claim 8 in which R₃ is t-butyl.
 16. A processaccording to claim 15 in which X is bromo or chloro.
 17. A processaccording to claim 16 in which Z is phenyl and L₁ and L₂ areindependently CH₂ CH₂.
 18. A compound of the formula: ##STR17## wherein:R₁ is CH₂ CH₂ --(L₁)_(p) --(CH₂)_(q) --(L₂)_(r) --CH₂ --(T)_(s) --Z;L₁and L₂ are independently CH₂ CH₂, CH═CH or C.tbd.C; q is 0 to 8; p, rand s are independently 0 or 1; T is O, S, CH₂, CH═CH, C.tbd.C; and Z isC₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl,cyclohexyl or phenyl optionally mono substituted with CF₃, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylthio, or trifluoromethylthio; R₂ and A areindependently H, CF₃, C₁₋₄ alkyl, F, Cl, Br or I; R₃ is C₁₋₆ alkyl, C₃₋₆cycloalkyl, (CH₂)_(t) phenyl or N(R')₂ ; R' is C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(t) phenyl; and t is
 1. 19. A compound according toclaim 18 in which R₃ is t-butyl.
 20. A compound according to claim 18 inWhich L₁ and L₂ are CH₂ CH₂ and Z is phenyl.
 21. A compound according toclaim 20 which isN-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethanamine.